Irradiation-induced dynamic changes of gene signatures reveal gain of metastatic ability in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC), arising from the nasopharynx epithelium, is prevalent among South and East Asia. The radiotherapy is the primary treatment for NPC patients. However, the acquired radioresistance dramatically diminishes the therapeutic effect of radiotherapy. Meanwhile, recurrence and metastasis always occur in line with the radioresistance, but the underlying mechanisms are still unclear. In this study, we established two radioresistant NPC cell lines, CNE1R and SUNE1R, by sequentially irradiated parental CNE1 and SUNE1 cells up to a clinical treatment dose of 72 Gy. A transcriptome profile analysis of CNE1R and CNE1 reveals that activated oncogenic pathways are highly enriched in CNE1R. As the result, CNE1R showed higher proliferation rate but lower apoptosis rate after irradiation, and enhanced metastasis ability in comparison with CNE1. Significantly, a group of metastasis associated genes were increased in CNE1R while the irradiation proceeded, including several matrix metallopeptidase (MMP) members, especially MMP10 and MMP13. With further analysis, we found both MMP10 and MMP13 are highly upregulated in metastatic head and neck cancer specimens compared to non-metastatic ones. More importantly, patients with lower expression of both MMP10 and MMP13 showed a better five-year survival than the double high group. Our findings unveiled the potential mechanisms of radioresistance related metastasis in NPC patients, and the increase of MMP10 and MMP13 may serve as high risk factors for metastasis during radiotherapy.